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2. The role of p21-activated kinase in the initiation of atherosclerosis

Author

Jhaveri K A, Debnath P, Chernoff J, Sanders J, and Schwartz M A

Subjects
Fluid shear stress, Endothelial cells, Vascular inflammation, Fibronectin, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Background p21-activated kinase (PAK) has been implicated in the inflammatory activation of endothelial cells by disturbed fluid shear stress, which is the initiating stimulus in atherosclerosis. The study addresses whether PAK1 contributes to inflammatory marker expression in endothelial cells at atherosclerosis-susceptible regions of arteries in vivo. Method Aortas from WT and PAK1-/- C57BL/6J mice on a normal chow diet were fixed, dissected and processed for immunohistochemistry using a panel of inflammatory markers. We visualized and quantified staining in the endothelium at the greater and lesser curvatures of the arch of aorta, as atherosclerosis-resistant and susceptible regions, respectively. Results Fibronectin, VCAM-1 and the activated RelA NF-κB subunit were localized to the lesser curvature and decreased in PAK1-/- mice. The activated RelB NF-κB subunit was also localized to the lesser curvature but was increased in PAK1-/- mice. Low levels of staining for ICAM-1 and the monocyte/macrophage marker Mac2 indicated that overall inflammation in this tissue was minimal. Conclusion These data show that PAK1 has a significant pro-inflammatory function at atherosclerosis-prone sites in vivo. These effects are seen in young mice with very low levels of inflammation, suggesting that inflammatory activation of the endothelium is primarily biomechanical. Activation involves NF-κB, expression of leukocyte recruitment receptors and fibronectin deposition. These results support and extend in vitro studies demonstrating that PAK contributes to activation of inflammatory pathways in endothelial cells by fluid shear stress.

Published
2012
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3. Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial

Author

Jhaveri, K., Eli, L.D., Wildiers, H., Hurvitz, S.A., Guerrero-Zotano, A., Unni, N., Brufsky, A., Park, H., Waisman, J., Yang, E.S., Spanggaard, I., Reid, S., Burkard, M.E., Vinayak, S., Prat, A., Arnedos, M., Bidard, F.-C., Loi, S., Crown, J., Bhave, M., Piha-Paul, S.A., Suga, J.M., Chia, S., Saura, C., Garcia-Saenz, J.Á., Gambardella, V., de Miguel, M.J., Gal-Yam, E.N., Raphael, A., Stemmer, S.M., Ma, C., Hanker, A.B., Ye, D., Goldman, J.W., Bose, R., Peterson, L., Bell, J.S.K., Frazier, A., DiPrimeo, D., Wong, A., Arteaga, C.L., and Solit, D.B.

Published
2023
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5. 187O Capivasertib and fulvestrant for patients (pts) with aromatase inhibitor (AI)-resistant HR+/HER2– advanced breast cancer (ABC): Subgroup analyses from the phase III CAPItello-291 trial

Author

Oliveira, M., primary, Rugo, H.S., additional, Howell, S.J., additional, Dalenc, F., additional, Cortés, J., additional, Moreno, H.L. Gomez, additional, Hu, X., additional, Jhaveri, K., additional, Loibl, S., additional, Morales, S., additional, Okera, M., additional, Park, Y.H., additional, Sohn, J., additional, Tokunaga, E., additional, Zhukova, L., additional, Wadsworth, I., additional, Schiavon, G., additional, Foxley, A., additional, and Turner, N., additional

Published
2023
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7. 196P Efficacy and safety of first-line (1L) ribociclib (RIB) + letrozole (LET) in patients (pts) with de novo metastatic disease and late recurrence from (neo)adjuvant therapy (tx) in MONALEESA (ML)-2

Author

O'Shaughnessy, J., primary, Beck, T., additional, Chia, S., additional, Isaacs, C., additional, De Laurentiis, M., additional, Kuemmel, S., additional, Jhaveri, K., additional, Janni, W., additional, Rugo, H.S., additional, Lteif, A., additional, Sopher, G., additional, Hu, H., additional, and Neven, P., additional

Published
2023
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9. Matching adjusted indirect comparison of PFS & OS comparing ribociclib + letrozole vs palbociclib + letrozole as first-line treatment of HR+/HER2− ABC: Analysis based on updated PFS & final OS results of MONALEESA-2 & PALOMA-2

Author

Jhaveri, K., primary, O’Shaughnessy, J., additional, Fasching, P., additional, Cardoso, F., additional, Tolaney, S., additional, Hamilton, E., additional, Sharma, V.K., additional, Biswas, C., additional, Haftchenary, S., additional, Pathak, P., additional, and Rugo, H., additional

Published
2022
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10. Neratinib efficacy in patients with EGFR exon 18-mutant non-small-cell lung cancer: findings from the SUMMIT basket trial

Author

Goldman, J., primary, Martínez Bueno, A., additional, Dooms, C., additional, Jhaveri, K., additional, de Miguel, M.J., additional, Piha-Paul, S.A., additional, Unni, N., additional, Mahipal, A., additional, Suga, J.M., additional, Naltet, C., additional, Zick, A., additional, Antoñanzas Basa, M., additional, Crown, J., additional, Chae, Y.K., additional, DiPrimeo, D., additional, Eli, L.D., additional, McCulloch, L., additional, and Mahalingam, D., additional

Published
2022
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11. LBA76 Overall survival (OS) results from the phase III TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician's choice (TPC) in patients (pts) with HR+/HER2- metastatic breast cancer (mBC)

Author

Rugo, H.S., primary, Bardia, A., additional, Marmé, F., additional, Cortés, J., additional, Schmid, P., additional, Loirat, D., additional, Tredan, O., additional, Ciruelos, E.M., additional, Dalenc, F., additional, Gomez Pardo, P., additional, Jhaveri, K., additional, Delaney, R.J., additional, Valdez, T., additional, Wang, H., additional, Verret, W., additional, and Tolaney, S.M., additional

Published
2022
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12. 460MO Preliminary results from a phase I study using the bispecific, human epidermal growth factor 2 (HER2)-targeting antibody-drug conjugate (ADC) zanidatamab zovodotin (ZW49) in solid cancers

Author

Jhaveri, K., primary, Han, H., additional, Dotan, E., additional, Oh, D-Y., additional, Ferrario, C., additional, Tolcher, A., additional, Lee, K-W., additional, Liao, C-Y., additional, Kang, Y-K., additional, Kim, Y.H., additional, Hamilton, E., additional, Spira, A., additional, Patel, N., additional, Karapetis, C., additional, Rha, S.Y., additional, Boyken, L., additional, Woolery, J., additional, and Bedard, P., additional

Published
2022
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13. 214MO Sacituzumab govitecan (SG) efficacy in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) metastatic breast cancer (MBC) by HER2 immunohistochemistry (IHC) status in the phase III TROPiCS-02 study

Author

Schmid, P., primary, Cortés, J., additional, Marmé, F., additional, Rugo, H.S., additional, Tolaney, S.M., additional, Oliveira, M., additional, Loirat, D., additional, Jhaveri, K., additional, Yoon, O.K., additional, Motwani, M., additional, Wang, H., additional, Delaney, R.J., additional, and Bardia, A., additional

Published
2022
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14. 437TiP An open-label, multicenter, phase II study to evaluate the safety and efficacy of BB-1701, a novel antibody drug conjugate (ADC) targeting HER2, in previously treated patients (pts) with HER2+ or HER2-low unresectable or metastatic (M) breast cancer (BC)

Author

George, M., Frenel, J-S., Cortés, J., Schmidt, M., Saenz, J.Á. García, Blau, S., Abdulla, N.E., Nishimura, M., Sakai, H., Babu, S., McAndrew, N.P., Ali, A., Pavic, M., Jhaveri, K., Jones, J.M., Rugo, H.S., Mody, K., Smith, A.D., and Yamashita, T.

Published
2024
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15. 431P Exposure-adjusted incidence rates (EAIRs) of adverse events (AEs) from the TROPION-Breast01 study of datopotamab deruxtecan (Dato-DXd) vs investigator’s choice of chemotherapy (ICC) in patients (pts) with pretreated, inoperable/metastatic HR+/HER2– breast cancer (BC)

Author

Rugo, H.S., Bardia, A., Im, S-A., Simon, S. Pernas, De Laurentiis, M., Wang, S., Martinez, N., Borges, G. Santos, Cescon, D., Hattori, M., Lu, Y-S., Tsurutani, J., Tolaney, S.M., Mapiye, D., Atuah, K., Verma, D., Khan, S., Xu, B., Pistilli, B., and Jhaveri, K.

Published
2024
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18. 175P Alpelisib (ALP) + endocrine therapy (ET) in patients (pts) with PIK3CA-mutated, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC): Subgroup analyses from the BYLieve study

Author

Cardoso, F., primary, Juric, D., additional, Lerebours, F., additional, Krop, I., additional, Ruiz Borrego, M., additional, Neven, P., additional, Park, Y.H., additional, Yardley, D., additional, Jhaveri, K., additional, Arce, C., additional, Gu, E., additional, Akdere, M., additional, and Rugo, H.S., additional

Published
2022
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21. A phase I/Ib study evaluating GDC-0077 (inavolisib) + palbociclib (palbo) + fulvestrant in patients (pts) with PIK3CA-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC)

Author

Schmid, P, additional, Bedard, PL, additional, Jhaveri, K, additional, Cervantes, A, additional, Gambardella, V, additional, Hamilton, E, additional, Italiano, A, additional, Kalinsky, K, additional, Krop, IE, additional, Oliveira, M, additional, Saura, C, additional, Turner, N, additional, Varga, A, additional, Hutchinson, K, additional, Lei, G, additional, Royer-Joo, S, additional, Thomas, P, additional, JL, Schutzman, additional, and Juric, D, additional

Published
2021
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22. Phase I Basket Study of Taselisib, an Isoform-Selective PI3K Inhibitor, in Patients with PIK3CA-Mutant Cancers

Author

Jhaveri K, Chang M, Juric D, Saura C, Gambardella V, Melnyk A, Patel M, Ribrag V, Ma C, Aljumaily R, Bedard P, Sachdev J, Dunn L, Won H, Bond J, Jones S, Savage H, Scaltriti M, Wilson T, Wei M, and Hyman D

Abstract

PURPOSE: Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), which encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K), are found in multiple human cancers. While recurrent mutations in PIK3CA helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with PIK3CA-mutant cancers with the isoform-specific PI3K inhibitor, taselisib. PATIENTS AND METHODS: Patients were enrolled based on local PIK3CA mutation testing into 1 of 11 histology-specific cohorts and treated with taselisib at 6 mg or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed. RESULTS: 166 patients with PIK3CA-mutant cancers were enrolled. The confirmed response rate was 9.0%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10.0%), and other cancers, plus tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront (TP53 and PTEN) and post-progression through reactivation of the PI3K pathway (PTEN, STK11, and PIK3R1). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index. CONCLUSIONS: Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target PIK3CA-mutant tumors.

Published
2021

23. Quality indicator selection for the Canadian Partnership against Cancer rectal cancer project: A modified Delphi study

Author

Pooni, A, Schmocker, S, Brown, C, MacLean, A, Hochman, D, Williams, L, Baxter, N, Simunovic, M, Liberman, S, Drolet, S, Neumann, K, Jhaveri, K, Kirsch, R, Kennedy, ED, Pooni, A, Schmocker, S, Brown, C, MacLean, A, Hochman, D, Williams, L, Baxter, N, Simunovic, M, Liberman, S, Drolet, S, Neumann, K, Jhaveri, K, Kirsch, R, and Kennedy, ED

Abstract

AIM: It is well established that (i) magnetic resonance imaging, (ii) multidisciplinary cancer conference (MCCs), (iii) preoperative radiotherapy, (iv) total mesorectal excision surgery and (v) pathological assessment as described by Quirke are key processes necessary for high quality, rectal cancer care. The objective was to select a set of multidisciplinary quality indicators to measure the uptake of these clinical processes in clinical practice. METHOD: A multidisciplinary panel was convened and a modified two-phase Delphi method was used to select a set of quality indicators. Phase 1 included a literature review with written feedback from the panel. Phase 2 included an in-person workshop with anonymous voting. The selection criteria for the indicators were strength of evidence, ease of capture and usability. Indicators for which ≥90% of the panel members voted 'to keep' were selected as the final set of indicators. RESULTS: During phase 1, 68 potential indicators were generated from the literature and an additional four indicators were recommended by the panel. During phase 2, these 72 indicators were discussed; 48 indicators met the 90% inclusion threshold and included eight pathology, five radiology, 11 surgical, six radiation oncology and 18 MCC indicators. CONCLUSION: A modified Delphi method was used to select 48 multidisciplinary quality indicators to specifically measure the uptake of key processes necessary for high quality care of patients with rectal cancer. These quality indicators will be used in future work to identify and address gaps in care in the uptake of these clinical processes.

Published
2021

25. LBA11 Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer (BC): Primary results from the randomised phase III TROPION-Breast01 trial

Author

Bardia, A., Jhaveri, K., Im, S-A., Pernas Simon, S., De Laurentiis, M., Wang, S., Martinez, N., Santos Borges, G., Cescon, D.W., Hattori, M., Lu, Y-S., Hamilton, E.P., Zhang, Q.Y., Tsurutani, J., Kalinsky, K., Xu, L., Denduluri, N., Rugo, H.S., Xu, B., and Pistilli, B.

Published
2023
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27. FP14.15 Neratinib-Based Combination Therapy in HER2-Mutant Lung Adenocarcinomas: Findings from two International Phase 2 Studies

Author

Li, B., primary, Gandhi, L., additional, Besse, B., additional, Jhaveri, K., additional, Mazières, J., additional, Boni, V., additional, Shapiro, G., additional, Waqar, S., additional, Viteri, S., additional, Park, H., additional, Quinn, D., additional, Stemmer, S., additional, Cortot, A., additional, Burkard, M., additional, Scaltriti, M., additional, Won, H., additional, Lalani, A., additional, Mcculloch, L., additional, Bebchuk, J., additional, Xu, F., additional, Bryce, R., additional, Meric-Bernstam, F., additional, Piha-Paul, S., additional, Solit, D., additional, and Janne, P., additional

Published
2021
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28. Efficacy and Determinants of Response to HER Kinase Inhibition in HER2-Mutant Metastatic Breast Cancer

Author

Smyth L, Piha-Paul S, Won H, Schram A, Saura C, Loi S, Lu J, Shapiro G, Juric D, Mayer I, Arteaga C, de la Fuente M, Brufksy A, Spanggaard I, Mau-Sorensen M, Arnedos M, Moreno V, Boni V, Sohn J, Schwartzberg L, Gonzalez-Farre X, Cervantes A, Bidard F, Gorelick A, Lanman R, Nagy R, Ulaner G, Chandarlapaty S, Jhaveri K, Gavrila E, Zimel C, Selcuklu S, Melcer M, Samoila A, Cai Y, Scaltriti M, Mann G, Xu F, Eli L, Dujka M, Lalani A, Bryce R, Baselga J, Taylor B, Solit D, Meric-Bernstam F, and Hyman D

Subjects
skin and connective tissue diseases
Abstract

HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. SIGNIFICANCE: HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer.

Published
2020

29. Risk of gallbladder cancer in patients with primary sclerosing cholangitis and radiographically detected gallbladder polyps

Author

Erp, L.W. van, Cunningham, M., Narasimman, M., Ali, H., Jhaveri, K., Drenth, J.P.H., Janssen, H.L., Levy, C., Hirschfield, G.M., Hansen, B.E., Gulamhusein, A.F., Erp, L.W. van, Cunningham, M., Narasimman, M., Ali, H., Jhaveri, K., Drenth, J.P.H., Janssen, H.L., Levy, C., Hirschfield, G.M., Hansen, B.E., and Gulamhusein, A.F.

Abstract

Contains fulltext : 220003.pdf (Publisher’s version ) (Closed access), BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is associated with an increased risk of gallbladder cancer (GBC). Gallbladder polyps potentially harbour malignancy and thus international guidelines recommend prophylactic cholecystectomy for gallbladder polyps of any size in patients with PSC. To best inform patient care we sought to quantify the malignant risk of gallbladder polyps in patients with PSC. METHODS: A retrospective cohort study of patients followed in secondary and tertiary care settings in two large PSC clinics in North America was performed. RESULTS: In total, 453 patients were included with a median (IQR) follow-up time of 7.7 (4.1-12) years. A gallbladder polyp was radiographically detected in 16% (n = 71) with median size (range) of 4 (2-18) mm. In this group, post-cholecystectomy histology (n = 17) reported benign or no polyp in 77% (n = 13), dysplasia in 5.9% (n = 1) and malignancy in 18% (n = 3). The GBC rate was 8.8 (95% CI 1.8-25.7) per 1000 person-years in patients with a radiographically detected gallbladder polyp. GBC was associated with polyps >10 mm, interval growth or mass-like lesions on pre-operative imaging. In patients who did not have cholecystectomy (n = 50), the polyp was only transiently seen in 80% (n = 40), remained stable or decreased in size in 10% (n = 5) and increased in size in 6% (n = 3). The majority of gallbladder polyps did not show significant growth over time (0.041 mm/year [95% CI -0.017 to 0.249]). CONCLUSIONS: Most gallbladder polyps in patients with PSC are benign. Short-term surveillance imaging may be considered prior to recommending immediate cholecystectomy in patients with PSC without high-risk imaging features.

Published
2020

30. The Canadian Partnership Against Cancer Rectal Cancer Project: Protocol for a Pan-Canadian, Multidisciplinary Quality Improvement Initiative to Optimize the Quality of Rectal Cancer Care

Author

Pooni, A, Schmocker, S, Brown, C, MacLean, A, Williams, L, Baxter, NN, Simunovic, M, Liberman, AS, Drolet, S, Neumann, K, Jhaveri, K, Kirsch, R, Kennedy, ED, Pooni, A, Schmocker, S, Brown, C, MacLean, A, Williams, L, Baxter, NN, Simunovic, M, Liberman, AS, Drolet, S, Neumann, K, Jhaveri, K, Kirsch, R, and Kennedy, ED

Abstract

BACKGROUND: Over the last 2 decades, the use of multimodal strategies, including total mesorectal excision (TME) surgery, preoperative chemotherapy, multidisciplinary case conference, pelvic magnetic resonance imaging, and pathologic assessment using Quirke method, has led to significant improvements in oncologic outcomes for patients with rectal cancer. Although the literature supports claims on the effectiveness of these multimodal strategies, the uptake of these multimodal strategies varies considerably among centers, suggesting that the best evidence is not always implemented into clinical practice. OBJECTIVE: This study aims to perform a quality improvement initiative to (1) identify existing gaps in care for these multimodal strategies and (2) implement knowledge translation (KT) interventions to close these gaps to optimize quality of care for patients with rectal cancer across high-volume centers in Canada. METHODS: Process indicators for the selected multimodal strategies to optimize rectal cancer care will be selected and prospectively collected for all patients with stages 1 to 3 rectal cancer undergoing TME surgery. KT interventions, including audit and feedback, opinion leaders, and community of practice, will be implemented to increase the uptake of these clinical strategies. RESULTS: The uptake of the process indicators over time and the effect of the uptake of the process indicators on short- and long-term oncologic outcomes will be evaluated for each multimodal strategy. CONCLUSIONS: This quality improvement initiative will identify existing gaps in care for the selected multimodal strategies and implement KT interventions to close these gaps. The results of this study will inform further efforts to optimize rectal cancer care. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15535.

Published
2020

35. 336P PI3K pathway biomarkers and clinical response in a phase I/Ib study of GDC-0077 in hormone receptor-positive/HER2-negative breast cancer (HR+/HER2– BC)

Author

Gambardella, V., primary, Cervantes, A., additional, Bedard, P.L., additional, Hamilton, E.P., additional, Italiano, A., additional, Jhaveri, K., additional, Juric, D., additional, Kalinsky, K., additional, Krop, I.E., additional, Oliveira, M., additional, Saura, C., additional, Schmid, P., additional, Turner, N., additional, Varga, A., additional, Liu, B.P., additional, Chen, J.W., additional, Aimi, J., additional, Royer-Joo, S., additional, Schutzman, J.L., additional, and Hutchinson, K.E., additional

Published
2020
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36. 350TiP A phase III trial of capivasertib and fulvestrant versus placebo and fulvestrant in patients with HR+/HER2− breast cancer (CAPItello-291)

Author

Turner, N., primary, Howell, S., additional, Jhaveri, K., additional, Gomez, H., additional, Toi, M., additional, Hu, X., additional, Loibl, S., additional, Rugo, H.S., additional, Ni, P., additional, De Bruin, E., additional, Orbegoso, C.M.A.A., additional, Schiavon, G., additional, Foxley, A., additional, and Oliveira, M., additional

Published
2020
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37. 355TiP Phase III study of GDC-0077 or placebo (pbo) with palbociclib (P) + fulvestrant (F) in patients (pts) with PIK3CA-mutant/hormone receptor-positive/HER2-negative locally advanced or metastatic breast cancer (HR+/HER2– LA/MBC)

Author

Turner, N., primary, Jhaveri, K., additional, Kalinsky, K., additional, Loibl, S., additional, Loi, S., additional, Im, S-A., additional, Saura, C., additional, Schmid, P., additional, Schutzman, J.L., additional, Stout, T., additional, Lei, G., additional, Hutchinson, K.E., additional, Thanopoulou, E., additional, and Juric, D., additional

Published
2020
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41. LBA1 Interim results of a phase I/Ib study of LSZ102, an oral selective estrogen receptor degrader (SERD), in combination with ribociclib (RIB) or alpelisib (ALP) in patients with ER+ breast cancer (BC) who had progressed after endocrine therapy (ET)

Author

Jhaveri, K., primary, Juric, D., additional, Yap, Y-S., additional, Cresta, S., additional, Layman, R., additional, Duhoux, F., additional, Terret, C., additional, De Vita, S., additional, Kundamal, N., additional, He, W., additional, Balbin, A., additional, Sheng, Q., additional, Crystal, A., additional, and Curigliano, G., additional

Published
2020
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45. Abstract P1-19-03: A phase I trial of sorafenib with whole brain radiotherapy (WBRT) in breast cancer patients with brain metastases and a correlative study of FLT-PET brain imaging in patients receiving WBRT with or without sorafenib

Author

Morikawa, A, primary, Jhaveri, K, additional, Grkovski, M, additional, Tang, K, additional, Humm, JL, additional, Holodny, A, additional, Beal, K, additional, Schoder, H, additional, and Seidman, AD, additional

Published
2019
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46. Abstract P6-20-03: Tumor epichaperome expression using 124I PU-H71 PET (PU-PET) as a biomarker of response for PU-H71 plus nab-paclitaxel in HER2 negative (HER2-) metastatic breast cancer (MBC)

Author

Jhaveri, K, primary, Dunphy, M, additional, Wang, R, additional, Comen, E, additional, Fornier, M, additional, Moynahan, ME, additional, Bromberg, J, additional, Ma, W, additional, Patil, S, additional, Taldone, T, additional, Rodina, A, additional, Sterlin, V, additional, Khoshi, S, additional, Lewis, J, additional, Norton, L, additional, Chiosis, G, additional, and Modi, S, additional

Published
2019
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47. Abstract OT1-03-01: Phase 1/1b study of novel oral selective estrogen receptor degrader (SERD) LSZ102 in combination with alpelisib (BYL719) in estrogen receptor-positive (ER+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC) with progression on endocrine therapy (ET)

Author

Curigliano, G, primary, Cresta, S, additional, Yap, Y-S, additional, Juric, D, additional, Duhoux, FP, additional, Terret, C, additional, Takahashi, S, additional, Layman, RM, additional, Kundamal, N, additional, Baldoni, D, additional, Liao, S, additional, Crystal, A, additional, and Jhaveri, K, additional

Published
2019
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48. Abstract PD1-08: Phase 1/1b study of novel oral selective estrogen receptor degrader (SERD) LSZ102 for estrogen receptor-positive (ER+) advanced breast cancer (ABC) with progression on endocrine therapy (ET)

Author

Jhaveri, K, primary, Curigliano, G, additional, Yap, Y-S, additional, Cresta, S, additional, Duhoux, FP, additional, Terret, C, additional, Takahashi, S, additional, Ulaner, GA, additional, Kundamal, N, additional, Baldoni, D, additional, Liao, S, additional, Crystal, A, additional, and Juric, D, additional

Published
2019
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49. Ganetespib: research and clinical development

Author

Jhaveri K and Modi S

Subjects
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282
Abstract

Komal Jhaveri, Shanu Modi Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA Abstract: Under stressful conditions, the heat shock protein 90 (HSP90) molecular chaperone protects cellular proteins (client proteins) from degradation via the ubiquitin-proteasome pathway. HSP90 expression is upregulated in cancers, and this contributes to the malignant phenotype of increased proliferation and decreased apoptosis and maintenance of metastatic potential via conservation of its client proteins, including human epidermal growth factor receptor 2, anaplastic lymphoma kinase, androgen receptor, estrogen receptor, Akt, Raf-1, cell cycle proteins, and B-cell lymphoma 2 among others. Hence, inhibition of HSP90 leads to the simultaneous degradation of its many clients, thereby disrupting multiple oncogenic signaling cascades. This has sparked tremendous interest in the development of HSP90 inhibitors as an innovative anticancer strategy. Based on the wealth of compelling data from preclinical studies, a number of HSP90 inhibitors have entered into clinical testing. However, despite enormous promise and anticancer activity reported to date, none of the HSP90 inhibitors in development has been approved for cancer therapy, and the full potential of this class of agents is yet to be realized. This article provides a review on ganetespib, a small molecule HSP90 inhibitor that is currently under evaluation in a broad range of cancer types in combination with other therapeutic agents with the hope of further enhancing its efficacy and overcoming drug resistance. Based on our current understanding of the complex HSP90 machinery combined with the emerging data from these key clinical trials, ganetespib has the potential to be the first-in-class HSP90 inhibitor to be approved as a new anticancer therapy. Keywords: HSP90, lung cancer, breast cancer, colorectal cancer

Published
2015

50. HER kinase inhibition in patients with HER2-and HER3-mutant cancers

Author

Hyman, DM, Piha-Paul, SA, Won, H, Rodon, J, Saura, C, Shapiro, GI, Juric, D, Quinn, DI, Moreno, V, Doger, B, Mayer, IA, Boni, V, Calvo, E, Loi, S, Lockhart, AC, Erinjeri, JP, Scaltriti, M, Ulaner, GA, Patel, J, Tang, J, Beer, H, Selcuklu, SD, Hanrahan, AJ, Bouvier, N, Melcer, M, Murali, R, Schram, AM, Smyth, LM, Jhaveri, K, Li, BT, Drilon, A, Harding, JJ, Iyer, G, Taylor, BS, Berger, MF, Cutler, RE, Xu, F, Butturini, A, Eli, LD, Mann, G, Farrell, C, Lalani, AS, Bryce, RP, Arteaga, CL, Meric-Bernstam, F, Baselga, J, Solit, DB, Hyman, DM, Piha-Paul, SA, Won, H, Rodon, J, Saura, C, Shapiro, GI, Juric, D, Quinn, DI, Moreno, V, Doger, B, Mayer, IA, Boni, V, Calvo, E, Loi, S, Lockhart, AC, Erinjeri, JP, Scaltriti, M, Ulaner, GA, Patel, J, Tang, J, Beer, H, Selcuklu, SD, Hanrahan, AJ, Bouvier, N, Melcer, M, Murali, R, Schram, AM, Smyth, LM, Jhaveri, K, Li, BT, Drilon, A, Harding, JJ, Iyer, G, Taylor, BS, Berger, MF, Cutler, RE, Xu, F, Butturini, A, Eli, LD, Mann, G, Farrell, C, Lalani, AS, Bryce, RP, Arteaga, CL, Meric-Bernstam, F, Baselga, J, and Solit, DB

Abstract

Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological importance by conducting a multi-histology, genomically selected, 'basket' trial using the pan-HER kinase inhibitor neratinib (SUMMIT; clinicaltrials.gov identifier NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours that contain kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to refine our biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.

Published
2018

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